PROJECT SUMMARY Cognitive impairments like over-perserveration, mental rigidity, and cognitive inflexibility accompany several neurological diseases ? most prominently, Parkinson's Disease (PD). PD is the second most common neurodegenerative disorder in humans. While it is a predominantly motor disorder, many PD patients experience cognitive symptoms. However, despite the broad incidence of impaired cognitive flexibility in PD and other disorders, little is known about the mechanistic neural underpinnings of this ability in health and disease. Hence, there is a critical need for a mechanistic neural theory of cognitive flexibility. In this grant proposal, we propose to test a working model of this ability, which centers on the role of a fronto-basal ganglia (FBg) brain mechanism for inhibition. We use a converging evidence approach that includes intracranial recordings from the basal ganglia, scalp EEG, motor systems measurements, and brain stimulation. The core hypothesis of the proposed model is that rapid cognitive flexibility depends on a neural mechanism for inhibitory control. Based on extensive pilot data, we propose that this mechanism allows healthy individuals to adaptively disengage from ongoing cognitive processes (working memory, task set representations, attentional focus, etc.). Importantly, the proposed neural mechanism is ? until now ? largely known as a motor inhibition mechanism: it can serve to stop already initiated actions by recruiting a network of FBg brain regions to inhibit motor activity. The circuitry underlying this inhibitory control mechanism is known to be damaged in PD, which is thought to explain some of its motor symptoms. Our proposal that this mechanism can serve to also inhibit cognition could explain why PD patients overpersevere on outdated cognitive processes: damage to the same mechanism whose malfunction impairs motor inhibition in PD may also impair cognitive flexibility. To test this model, the first of group of studies in this proposal is designed to identify the types of situations in which the inhibitory FBg mechanism is engaged. Specifically, neural and motor signatures of the inhibitory FBg mechanism will be measured across different types of situations that require rapid cognitive control (errors, response-conflict, unexpected perceptual events). The goal is to investigate whether the mechanism is active in a broad array of scenarios that demand rapid cognitive flexibility. The second group of studies aims to investigate the potential inhibitory influence of the FBg mechanism on cognitive representations. Specifically, activity of the FBg mechanism will be measured in a new battery of tasks designed to test how ongoing task set representations and attentional processes are interrupted when necessary. The goal is to test the core proposition of the model, namely, that the FBg mechanism's inhibitory capacity extends beyond the motor system, and can affect active cognitive representations. The final group of studies will test the effects of different types of brain stimulation on the inhibitory FBg mechanism's ability to inhibit ongoing cognitive representations. These studies aim to provide causal evidence for the model and translate it into clinical practice.